Volume 545 Number 7653

Editorials

News

News Features

News & Views

Subclone wars p.160

Pluripotent stem cells, which give rise to every cell type, can acquire cancer-causing genetic mutations when grown in vitro. This finding has implications for the use of pluripotent cells in basic research and in the clinic. See Letter p.229

doi: 10.1038/nature22490

Asian glaciers are a reliable water source p.161

The people, economies and agriculture of central Asia and parts of south Asia rely on water from mountains. Modelling suggests that glacier melt, in particular, is a key water source during dry periods in some of these regions. See Letter p.169

doi: 10.1038/545161a

An ion-transport enzyme that rocks p.162

Previous crystal structures of membrane-spanning enzymes called ATPases have revealed that the enzymes undergo complex movements. The movements, it now emerges, involve rocking in place in the membrane. See Article p.193

doi: 10.1038/nature22492

Atomic envoy enables molecular control p.164

A technique for manipulating molecules uses an intermediary atom to query a nearby molecule's energy state and produces 'quantum superpositions' of these states, a prerequisite for extremely high-precision spectroscopy. See Letter p.203

doi: 10.1038/545164a

The long and short of a DNA-damage response p.165

Ultraviolet light can damage DNA, triggering a general shutdown of gene transcription — yet some genes are activated by UV light. An investigation of this counter-intuitive behaviour reveals a surprising gene-regulation mechanism.

doi: 10.1038/nature22488

A social spin on language analysis p.166

Understanding the prevalence and impact of personal attacks in online discussions is challenging. A method that combines crowdsourcing and machine learning provides a way forward, but caveats must be considered.

doi: 10.1038/545166a

Articles

Letters

Decarboxylative alkenylation p.213

Starting with alkyl carboxylic acids, a simple olefin synthesis using any substitution pattern or geometry, based on amide-bond synthesis with nickel- or iron-based catalysis, is described.

doi: 10.1038/nature22307

Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling p.234

Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD–LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

doi: 10.1038/nature22306

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal p.238

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

doi: 10.1038/nature22313